Process of making alkyl ethers of morphin.



TEnsTK'rEs,

PATENT orrron.

LUDWIG H. REUTER, OF NEW YORK, N. Y.

Specification of Letters Patent.

Patented Jan. 22, 1907.

Application filed March 19, 1906- Serial No. 306,909.

To all tyhom it may concern:

Be it known that I, Lunwie H. REUTER, a subject-of the King of Bavaria,residing at the borough of Brooklyn, in the city of New York and Stateof New York, have invented a new and useful Process of Making AlkylEthers of Morphin, of which the following is a specification.

My invention relates to an improved process for preparing any for thealkyl ethers of morphinsuch as codein, &c.the principal objects being toprovide a method which can be carried out without incurring a loss of amaterial proportion of morphin by oxidation and to provide for theaction of the alkylizing agent or agents upon the major portion of themorphin employed, thus avoiding the enormous losses which haveheretofore been necessary in all methods of manufacturing alkyl ethersof morphin of which I am aware.

In the methods heretofore known the quantities of codein or otherproduct to be obtained, which from the molecular formulas might beassumed to be produced, have never been obtained, owing, chiefly, to thefact that a part of the morphin is oxidized in alkaline solution andconverted into products which are practically worthless and of courseresult in a loss of valuable material, and, secondly, because the sodiumhydrate which is used in many of these processes has a decomposingefiect on alkalyzing agents, such as trimethyl phosphate and methylnitrate, respectively, converting them into methyl alcohol and sodiummethyl phosphate and nitrate, respectively. Obviously not much codeincan be formed under such conditions.

In other processes in which morphinhydrate is employed decompositionsnecessarily take place which do not allow the formation of large yieldsof codein.

In order to prevent the oxidation of morphin, I have adopted severalmethods. For example, I have passed carbon-monoxid gas previously driedand freed from carbonic acid into a container holding the alkalinemorphin solution, thereby excluding all the air from the container inwhich the conversion of morphin into codein is carried on. This reducedthe oxidation of morphin by about twenty per cent. I have also secured areduction in oxidation by using hydrogen gas carefully dried and freedfrom carbonic acid and by using air freed from oxygen; but in noneofthese cases have I succeeded in cutting down the oxidation ofthe'morphin more than one-half of that experienced ordinarily in thesynthesis of alkyl derivatives of morphin. I have discov ered, however,that a number of organic substances known for their reducing powerespecially in alkaline solution when added in small proportions to thealkylizing agent produce most remarkable effects and that thenon-converted morphincan be almost quantitatively recovered without losson account of oxidation, only such a very slight loss being incurred asis due to the various digesting, extracting, evaporating, and otherprocesses to which the-morphin solutions are subjected. Among the agentswhich can be used for this purpose with satisfactory results are theorganic esters of the several alkyls, especially pure alkyl oxalates.

I have found that the methyl oxalate, bein a solid and odorlesssubstance whichcrys ta li'zes from benzene in beautifullarge crystalsandcan be manufactured at a low price in pure condition, is an articleof great stability and can be easily weighed and handled. I havediscovered also that it possesses two great advantages and performs twofunction's-namely, it prevents the oxidation of morphin in alkalinesolutions in processes of this character, and it. acts as an alkylizer,(methylizen) The use of these oxalates when added in small roportions offrom five to ten parts to one iundred parts of any of the well-knownalkylizin agents, such as v the nitrates or sulfates of al yl, preventsthe oxidation of morphin, and the nonconverted portion of morphin isrecoverable almost quantitatively in ure condition, consequently beingmuch lig ter in color than usual and capable of use in new operationswithout further purification. Anhydrous salts of pyrogallic acid,sulfites, and sodium oxymethyl sulfonate also prevent the oxidation ofmorphin. I have discovered also that for the purpose of getting largeyields of codein it is necessary to use exclusively anhydrousmaterialsfor instance, a mixture of methyl oxalate with trimethylphosphate or of methyl oxalate with dimethyl sulfate only in connectionwith anhydrous materials-such as anhydrous morphin, anhydrous methyl orethyl alcohol, and anhydrous alkali, such as sodium methylate oralcoholate. In this connection it may be stated that this point in myprocess differs from certain of those heretofore known on account oftheir using morphin hydrate and sodium hydrate in connection with themethylizing agent, both of which would introduce elements which it is mypurpose to avoid. Neither morphin hydrate nor sodium hydrate nor anyother hydrate compound nor alcohol containing moisture can beefliciently employed in my process, as the water would first decomposethe sodium methylate or alcoholate, and the sodium hydrate thus formedwould decompose my alkylizing agent comprising oxalate and dimethylsulfate.

In general it may be stated that the'preferred way of carrying out myprocess involves the treatment of anhydrous morphin dissolved in ananhydrous methyl or ethyl alcohol with a dry alkali methylate or in somecases alcoholate or other similar composition containing an alkali metalin the presence of an alkylizing agent consisting of an inorganic acidester of an alkyl and a small proportion of a neutral organic oxygenacid ester of an alkyl.

, As an example of manufacture I dissolve one thousand parts, by weight,of morphin .which has been made anhydrous by entirely not above 50 to'60centigrade, together with one hundred and eighty-eight parts, by weight,of dry sodium methylate or the proportionate quantity of dry sodiumalcoholate, which is formed when metallic sodium is dissolved inalcohol, three parts, by weight, of anhydrous methyl oxalate and fortyparts of anhydrous dimethyl sulfate in seven thousand parts, by weight,of anhydrous methyl or ethyl alcohol and digest the mixture until thereaction is finishedthat is, until the quantities of codein and morphin,as found by analysis of samples taken from time to time, remainconstant. The codein formed is separated in the usual way, while thenonconverted morphin is recovered practically quantitatively and freefrom oxidation products. I also find that when neutral inor anic acidesters of an alkyl, as dimetliyl sul 'te or trimethyl phosphite, areused with or without dimethyl sulfate'the same dry anhydrous conditionshould be preserved to secure the highest efficiency in the process.

Instead of the dimethyl sulfate or in connection with it, methylnitrate, trimethyl phosphate, and dimethyl sulfite or other materialsfor preventing the oxidation of morphin can be used with dry anhydrousmaterials, of course.

While I have described my invention as carried out with the use ofcertain chemical compounds, I am aware that modifications may be made inthe processby the substitution of other chemical substances foraccomplishing the same result by any person skilled in the art withoutdeparting from the scope of the invention as expressed in the claims.Therefore I do not wish to be limited to the exact substances mentioned;but

What I do claim, and desire to secure by Letters Patent, is

1. A process of manufacturing anhydrous alkyl ethers of morphin, whichcomprises treating a solution of anhydrous morphin with an anhydrousalkylizing agent all materials and products being anhydrous.

2. A process of making alkyl ethers of morphin, which comprises thetreatment of a solution of anhydrous morphin with an alkylizing agent inthe presence of an organic ester of an alkyl, all materials and productsbeing anhydrous.

3. A process of making alkyl ethers of morphin, which comprises thetreatment of a solution of anhydrous morphin with an alkylizing agent inthe presence of methyl oxalate, all materials and products beinganhydrous.

4. A process of manufacturing alkyl ethers of morphin, which comprisestreating anhydrous morphin dissolved in an anhydrous alcohol with ananhydrous inorganic acid ester of an alkyl and an anhydrous neutralorganic oxygen acid ester of an alkyl.

5. A process of manufacturing alkyl ethers of morphin, which comprisestreating anhydrous morphin dissolved in an anhpdrous alcohol with ananhydrous neutral 3. kyl ester of sulfuric acid and an anhydrous alkylester of oxalic acid in the presence of sodium.

6. A process of manufacturing alkyl ethers of morphin, which comprisestreating with a mixture of methyl oxalate and an alkyl sulfate, asolution of anhydrous morphin in an anhydrous alcohol in the presence ofa substance containing alkali metal.

7. A process of manufacturing alkyl ethers of morphin, which comprisesdissolving anhydrous morphin in an anhydrous alcohol in the presence ofa substance containing sodium, and then acting on that solution with amixture of anhydrous methyl oxalate and anhydrous dimethyl sulfate.

8. A process of manufacturing alkyl ethers of morphin, which comprisesdissolving anhydrous morphin in an anhydrous alcohol in the presence ofa substance containing an alkali metal, and then acting on that solutionwith anhydrous dimethyl sulfate in the presence of a substance forpreventing the oxidation of the morphin.

9. A process of manufacturing alkyl ethers of morphin, which comprisesthe addition of its an anhydrous alkyl oxalate to an anhydrousalkylizing agent and treating anhydrous morphin therewith.

10. A process of manufacturing alkyl ethers of morphin, which comprisesthe treatment 0 a so fition Yanhfdrous morphin with an alkylizing agentin the presence of a sub stance for preventing the oxidation of themorphin, all materials and products being anhydrous.

1 1 .-A process of manufacturing alkyl ethers of morphin, whichcomprises the treatment of a solution of anhydrous morphin with analkylizing agent in the presence of a substance for preventing theoxidation of the morphin and for assisting in the alkylizing action allmaterials and products being anhydrous.

12. A process of manufacturing alkyl ethers of morphin, which comprisesthe treatment of a solution of anhydrous morphin with dimethyl sulfatein the presence of a substance for preventing the oxidation of themorphin all materials and products being an 20 hydrous.

13. A rocess of manufacturing alkyl ethers of morphin, which comprisesthe treatment of anhydrous morphin dissolved in an anhydrous alcoholwith an anhydrous substance containing an alkali-metal in the presenceof an alkylizing agent, consisting of an inorganic acid ester of analkyl, and a neutral organic acid ester of an alkyl.

14. A process of preparing alkyl ethers of morphin, which comprisesacting upon anhydrous morphin by an anhydrous alkylizing agent in thepresence of an anhydrous organic reducing agent.

In testimony whereof I have hereunto set my hand in the presence of twosubscribing witnesses.

LUDWIG H. REUTER. Witnesses:

LEIGH DORNBURGH, CELIA STEINBERG.

